Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100

Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGFA). Although this drug has broad anti-tumour properties, there are no validated biomarkers to predict which subgroup of patients will respond or experience toxicity. The inability to enrich for the optimal population has been a barrier to maximum success. To date, bevacizumab has demonstrated clinically meaningful activity in colon cancer (Hurwitz et al, 2004), lung cancer (Sandler et al, 2006), renal-cell cancer (Yang et al, 2003), cervical cancer (Tewari et al, 2013) and glioblastoma multiforme (Walter Taal et al, 2013). Bevacizumab also gained accelerated US-FDA approval for metastatic breast cancer based, in part, on the results of ECOG-2100 (Miller et al, 2007), a randomised phase III trial of paclitaxel with or without bevacizumab. On the basis of less absolute differences in progression-free survival in later trials (AVADO, RIBBON-I, and RIBBON-II (Miles et al, 2010; Brufsky et al, 2011; Robert et al, 2011)), no overall survival benefit, and due to the unique and unpredictable toxicity profile, bevacizumab's US-FDA approval for breast cancer was rescinded (FDA NEWS RELEASE, 2011). Despite this, bevacizumab has remained an approved treatment for breast cancer in the European Union. The early success of bevacizumab in the metastatic setting led to the development of ECOG-5103, which tested a standard backbone of chemotherapy with concurrent or concurrent plus sequential bevacizumab in the adjuvant setting with results pending maturation of efficacy data. Two other phase-III adjuvant breast cancer trials, BETH and BEATRICE (Cameron et al, 2013; Slamon et al, 2013), have been negative, highlighting the limitations of bevacizumab for breast cancer in the absence of a successful efficacy marker. A major limitation of bevacizumab across all cancer types has been the inability to predict a priori which patients are most likely to obtain substantial benefit or toxicity from treatment (Schneider and Sledge, 2011). Validated biomarkers to predict either the efficacy or toxicity of bevacizumab are lacking, although germline DNA variants have been previously nominated (Schneider et al, 2012). Hypertension is the most common, serious bevacizumab-induced toxicity, which can occasionally be life threatening. Herein we have identified and validated a genetic biomarker for bevacizumab-induced hypertension in the adjuvant breast cancer trial, ECOG-5103 (whose efficacy data were not yet available for this analysis) and the metastatic breast cancer trial, ECOG-2100.